<!doctype html>
<html>
<head>
<!-- Global site tag (gtag.js) - Google Analytics -->
<script async src="https://www.googletagmanager.com/gtag/js?id=UA-114672259-1"></script>
<script>
  window.dataLayer = window.dataLayer || [];
  function gtag(){dataLayer.push(arguments);}
  gtag('js', new Date());
  gtag('config', 'UA-114672259-1');
  gtag('set', {'user_id': 'USER_ID'});
</script>
<meta charset='UTF-8'><meta name='viewport' content='width=device-width initial-scale=1'>
<title>21三代测序研究焦点⓷人类生物医学研究.md</title><link href='https://fonts.googleapis.com/css?family=Open+Sans:400italic,700italic,700,400&subset=latin,latin-ext' rel='stylesheet' type='text/css' /><style type='text/css'>html {overflow-x: initial !important;}:root { --bg-color:  #ffffff; --text-color:  #333333; --code-block-bg-color: inherit; }
html { font-size: 14px; background-color: var(--bg-color); color: var(--text-color); font-family: "Helvetica Neue", Helvetica, Arial, sans-serif; -webkit-font-smoothing: antialiased; }
body { margin: 0px; padding: 0px; height: auto; bottom: 0px; top: 0px; left: 0px; right: 0px; font-size: 1rem; line-height: 1.42857143; overflow-x: hidden; background-image: inherit; background-size: inherit; background-attachment: inherit; background-origin: inherit; background-clip: inherit; background-color: inherit; background-position: inherit inherit; background-repeat: inherit inherit; }
a:active, a:hover { outline: 0px; }
.in-text-selection, ::selection { background-color: rgb(181, 214, 252); text-shadow: none; background-position: initial initial; background-repeat: initial initial; }
#write { margin: 0px auto; height: auto; width: inherit; word-break: normal; word-wrap: break-word; position: relative; padding-bottom: 70px; white-space: pre-wrap; overflow-x: visible; }
.for-image #write { padding-left: 8px; padding-right: 8px; }
body.typora-export { padding-left: 30px; padding-right: 30px; }
@media screen and (max-width: 500px) { 
  body.typora-export { padding-left: 0px; padding-right: 0px; }
  .CodeMirror-sizer { margin-left: 0px !important; }
  .CodeMirror-gutters { display: none !important; }
}
.typora-export #write { margin: 0px auto; }
#write > p:first-child, #write > ul:first-child, #write > ol:first-child, #write > pre:first-child, #write > blockquote:first-child, #write > div:first-child, #write > table:first-child { margin-top: 30px; }
#write li > table:first-child { margin-top: -20px; }
img { max-width: 100%; vertical-align: middle; }
input, button, select, textarea { color: inherit; font-family: inherit; font-size: inherit; font-style: inherit; font-variant-caps: inherit; font-weight: inherit; font-stretch: inherit; line-height: inherit; }
input[type="checkbox"], input[type="radio"] { line-height: normal; padding: 0px; }
::before, ::after, * { box-sizing: border-box; }
#write p, #write h1, #write h2, #write h3, #write h4, #write h5, #write h6, #write div, #write pre { width: inherit; }
#write p, #write h1, #write h2, #write h3, #write h4, #write h5, #write h6 { position: relative; }
h1 { font-size: 2rem; }
h2 { font-size: 1.8rem; }
h3 { font-size: 1.6rem; }
h4 { font-size: 1.4rem; }
h5 { font-size: 1.2rem; }
h6 { font-size: 1rem; }
p { -webkit-margin-before: 1rem; -webkit-margin-after: 1rem; -webkit-margin-start: 0px; -webkit-margin-end: 0px; }
.typora-export p { white-space: normal; }
.mathjax-block { margin-top: 0px; margin-bottom: 0px; -webkit-margin-before: 0rem; -webkit-margin-after: 0rem; }
.hidden { display: none; }
.md-blockmeta { color: rgb(204, 204, 204); font-weight: bold; font-style: italic; }
a { cursor: pointer; }
sup.md-footnote { padding: 2px 4px; background-color: rgba(238, 238, 238, 0.701961); color: rgb(85, 85, 85); border-top-left-radius: 4px; border-top-right-radius: 4px; border-bottom-right-radius: 4px; border-bottom-left-radius: 4px; }
#write input[type="checkbox"] { cursor: pointer; width: inherit; height: inherit; margin: 4px 0px 0px; }
#write > figure:first-child { margin-top: 16px; }
figure { overflow-x: auto; margin: -8px 0px 0px -8px; max-width: calc(100% + 16px); padding: 8px; }
tr { break-inside: avoid; break-after: auto; }
thead { display: table-header-group; }
table { border-collapse: collapse; border-spacing: 0px; width: 100%; overflow: auto; break-inside: auto; text-align: left; }
table.md-table td { min-width: 80px; }
.CodeMirror-gutters { border-right-width: 0px; background-color: inherit; }
.CodeMirror { text-align: left; }
.CodeMirror-placeholder { opacity: 0.3; }
.CodeMirror pre { padding: 0px 4px; }
.CodeMirror-lines { padding: 0px; }
div.hr:focus { cursor: none; }
pre { white-space: pre-wrap; }
.CodeMirror-gutters { margin-right: 4px; }
.md-fences { font-size: 0.9rem; display: block; break-inside: avoid; text-align: left; overflow: visible; white-space: pre; background: var(--code-block-bg-color); position: relative !important; }
.md-diagram-panel { width: 100%; margin-top: 10px; text-align: center; padding-top: 0px; padding-bottom: 8px; overflow-x: auto; }
.md-fences .CodeMirror.CodeMirror-wrap { top: -1.6em; margin-bottom: -1.6em; }
.md-fences.mock-cm { white-space: pre-wrap; }
.show-fences-line-number .md-fences { padding-left: 0px; }
.show-fences-line-number .md-fences.mock-cm { padding-left: 40px; }
.CodeMirror-line { break-inside: avoid; }
.footnotes { opacity: 0.8; font-size: 0.9rem; padding-top: 1em; padding-bottom: 1em; }
.footnotes + .footnotes { margin-top: -1em; }
.md-reset { margin: 0px; padding: 0px; border: 0px; outline: 0px; vertical-align: top; background-color: transparent; text-decoration: none; text-shadow: none; float: none; position: static; width: auto; height: auto; white-space: nowrap; cursor: inherit; line-height: normal; font-weight: normal; text-align: left; box-sizing: content-box; direction: ltr; background-position: initial initial; background-repeat: initial initial; }
li div { padding-top: 0px; }
blockquote { margin: 1rem 0px; }
li p, li .mathjax-block { margin: 0.5rem 0px; }
li { margin: 0px; position: relative; }
blockquote > :last-child { margin-bottom: 0px; }
blockquote > :first-child { margin-top: 0px; }
.footnotes-area { color: rgb(136, 136, 136); margin-top: 0.714rem; padding-bottom: 0.143rem; }
@media print { 
  html, body { border: 1px solid transparent; height: 99%; break-after: avoid-page; break-before: avoid-page; }
  .typora-export * { -webkit-print-color-adjust: exact; }
  h1, h2, h3, h4, h5, h6 { break-after: avoid-page; orphans: 2; }
  p { orphans: 4; }
  html.blink-to-pdf { font-size: 13px; }
  .typora-export #write { padding-left: 1cm; padding-right: 1cm; padding-bottom: 0px; break-after: avoid-page; }
  .typora-export #write::after { height: 0px; }
  @page { margin: 20mm 0mm; }
}
.footnote-line { margin-top: 0.714em; font-size: 0.7em; }
a img, img a { cursor: pointer; }
pre.md-meta-block { font-size: 0.8rem; min-height: 2.86rem; white-space: pre-wrap; background-color: rgb(204, 204, 204); display: block; overflow-x: hidden; background-position: initial initial; background-repeat: initial initial; }
p > img:only-child { display: block; margin: auto; }
p .md-image:only-child { display: inline-block; width: 100%; text-align: center; }
#write .MathJax_Display { margin: 0.8em 0px 0px; }
.mathjax-block { white-space: pre; overflow: hidden; width: 100%; }
p + .mathjax-block { margin-top: -1.143rem; }
.mathjax-block:not(:empty)::after { display: none; }
[contenteditable="true"]:active, [contenteditable="true"]:focus { outline: none; box-shadow: none; }
.task-list { list-style-type: none; }
.task-list-item { position: relative; padding-left: 1em; }
.task-list-item input { position: absolute; top: 0px; left: 0px; }
.math { font-size: 1rem; }
.md-toc { min-height: 3.58rem; position: relative; font-size: 0.9rem; border-top-left-radius: 10px; border-top-right-radius: 10px; border-bottom-right-radius: 10px; border-bottom-left-radius: 10px; }
.md-toc-content { position: relative; margin-left: 0px; }
.md-toc::after, .md-toc-content::after { display: none; }
.md-toc-item { display: block; color: rgb(65, 131, 196); }
.md-toc-item a { text-decoration: none; }
.md-toc-inner:hover { }
.md-toc-inner { display: inline-block; cursor: pointer; }
.md-toc-h1 .md-toc-inner { margin-left: 0px; font-weight: bold; }
.md-toc-h2 .md-toc-inner { margin-left: 2em; }
.md-toc-h3 .md-toc-inner { margin-left: 4em; }
.md-toc-h4 .md-toc-inner { margin-left: 6em; }
.md-toc-h5 .md-toc-inner { margin-left: 8em; }
.md-toc-h6 .md-toc-inner { margin-left: 10em; }
@media screen and (max-width: 48em) { 
  .md-toc-h3 .md-toc-inner { margin-left: 3.5em; }
  .md-toc-h4 .md-toc-inner { margin-left: 5em; }
  .md-toc-h5 .md-toc-inner { margin-left: 6.5em; }
  .md-toc-h6 .md-toc-inner { margin-left: 8em; }
}
a.md-toc-inner { font-size: inherit; font-style: inherit; font-weight: inherit; line-height: inherit; }
.footnote-line a:not(.reversefootnote) { color: inherit; }
.md-attr { display: none; }
.md-fn-count::after { content: "."; }
.md-tag { opacity: 0.5; }
pre, code, tt { font-family: var(--monospace); }
.md-comment { color: rgb(162, 127, 3); opacity: 0.8; font-family: var(--monospace); }
code { text-align: left; }
h1 .md-tag, h2 .md-tag, h3 .md-tag, h4 .md-tag, h5 .md-tag, h6 .md-tag { font-weight: initial; opacity: 0.35; }
a.md-print-anchor { border: none !important; display: inline-block !important; position: absolute !important; width: 1px !important; right: 0px !important; outline: none !important; background-color: transparent !important; text-shadow: initial !important; background-position: initial initial !important; background-repeat: initial initial !important; }
.md-inline-math .MathJax_SVG .noError { display: none !important; }
.mathjax-block .MathJax_SVG_Display { text-align: center; margin: 1em 0em; position: relative; text-indent: 0px; max-width: none; max-height: none; min-height: 0px; min-width: 100%; width: auto; display: block !important; }
.MathJax_SVG_Display, .md-inline-math .MathJax_SVG_Display { width: auto; margin: inherit; display: inline-block !important; }
.MathJax_SVG .MJX-monospace { font-family: monospace; }
.MathJax_SVG .MJX-sans-serif { font-family: sans-serif; }
.MathJax_SVG { display: inline; font-style: normal; font-weight: normal; line-height: normal; zoom: 90%; text-indent: 0px; text-align: left; text-transform: none; letter-spacing: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; }
.MathJax_SVG * { transition: none; }
.md-diagram-panel > svg { max-width: 100%; }
[lang="flow"] svg, [lang="mermaid"] svg { max-width: 100%; }
table tr th { border-bottom-width: 0px; }


:root {
    --side-bar-bg-color: #fafafa;
    --control-text-color: #777;
}

@include-when-export url(https://fonts.googleapis.com/css?family=Open+Sans:400italic,700italic,700,400&subset=latin,latin-ext);

@font-face {
    font-family: 'Open Sans';
    font-style: normal;
    font-weight: normal;
    src: local('Open Sans Regular'),url('file:///Users/lx/Library/Application%20Support/abnerworks.Typora/themes/github/400.woff') format('woff')
}

@font-face {
    font-family: 'Open Sans';
    font-style: italic;
    font-weight: normal;
    src: local('Open Sans Italic'),url('file:///Users/lx/Library/Application%20Support/abnerworks.Typora/themes/github/400i.woff') format('woff')
}

@font-face {
    font-family: 'Open Sans';
    font-style: normal;
    font-weight: bold;
    src: local('Open Sans Bold'),url('file:///Users/lx/Library/Application%20Support/abnerworks.Typora/themes/github/700.woff') format('woff')
}

@font-face {
    font-family: 'Open Sans';
    font-style: italic;
    font-weight: bold;
    src: local('Open Sans Bold Italic'),url('file:///Users/lx/Library/Application%20Support/abnerworks.Typora/themes/github/700i.woff') format('woff')
}

html {
    font-size: 16px;
}

body {
    font-family: "Open Sans","Clear Sans","Helvetica Neue",Helvetica,Arial,sans-serif;
    color: rgb(51, 51, 51);
    line-height: 1.6;
}

#write{
    max-width: 860px;
  	margin: 0 auto;
  	padding: 20px 30px 40px 30px;
	padding-top: 20px;
    padding-bottom: 100px;
}
#write > ul:first-child,
#write > ol:first-child{
    margin-top: 30px;
}

body > *:first-child {
    margin-top: 0 !important;
}
body > *:last-child {
    margin-bottom: 0 !important;
}
a {
    color: #4183C4;
}
h1,
h2,
h3,
h4,
h5,
h6 {
    position: relative;
    margin-top: 1rem;
    margin-bottom: 1rem;
    font-weight: bold;
    line-height: 1.4;
    cursor: text;
}
h1:hover a.anchor,
h2:hover a.anchor,
h3:hover a.anchor,
h4:hover a.anchor,
h5:hover a.anchor,
h6:hover a.anchor {
    /*background: url("file:///Users/lx/Library/Application%20Support/images/modules/styleguide/para.png") no-repeat 10px center;*/
    text-decoration: none;
}
h1 tt,
h1 code {
    font-size: inherit;
}
h2 tt,
h2 code {
    font-size: inherit;
}
h3 tt,
h3 code {
    font-size: inherit;
}
h4 tt,
h4 code {
    font-size: inherit;
}
h5 tt,
h5 code {
    font-size: inherit;
}
h6 tt,
h6 code {
    font-size: inherit;
}
h1 {
    padding-bottom: .3em;
    font-size: 2.25em;
    line-height: 1.2;
    border-bottom: 1px solid #eee;
}
h2 {
   padding-bottom: .3em;
    font-size: 1.75em;
    line-height: 1.225;
    border-bottom: 1px solid #eee;
}
h3 {
    font-size: 1.5em;
    line-height: 1.43;
}
h4 {
    font-size: 1.25em;
}
h5 {
    font-size: 1em;
}
h6 {
   font-size: 1em;
    color: #777;
}
p,
blockquote,
ul,
ol,
dl,
table{
    margin: 0.8em 0;
}
li>ol,
li>ul {
    margin: 0 0;
}
hr {
    height: 4px;
    padding: 0;
    margin: 16px 0;
    background-color: #e7e7e7;
    border: 0 none;
    overflow: hidden;
    box-sizing: content-box;
    border-bottom: 1px solid #ddd;
}

body > h2:first-child {
    margin-top: 0;
    padding-top: 0;
}
body > h1:first-child {
    margin-top: 0;
    padding-top: 0;
}
body > h1:first-child + h2 {
    margin-top: 0;
    padding-top: 0;
}
body > h3:first-child,
body > h4:first-child,
body > h5:first-child,
body > h6:first-child {
    margin-top: 0;
    padding-top: 0;
}
a:first-child h1,
a:first-child h2,
a:first-child h3,
a:first-child h4,
a:first-child h5,
a:first-child h6 {
    margin-top: 0;
    padding-top: 0;
}
h1 p,
h2 p,
h3 p,
h4 p,
h5 p,
h6 p {
    margin-top: 0;
}
li p.first {
    display: inline-block;
}
ul,
ol {
    padding-left: 30px;
}
ul:first-child,
ol:first-child {
    margin-top: 0;
}
ul:last-child,
ol:last-child {
    margin-bottom: 0;
}
blockquote {
    border-left: 4px solid #dddddd;
    padding: 0 15px;
    color: #777777;
}
blockquote blockquote {
    padding-right: 0;
}
table {
    padding: 0;
    word-break: initial;
}
table tr {
    border-top: 1px solid #cccccc;
    margin: 0;
    padding: 0;
}
table tr:nth-child(2n) {
    background-color: #f8f8f8;
}
table tr th {
    font-weight: bold;
    border: 1px solid #cccccc;
    border-bottom: 0;
    text-align: left;
    margin: 0;
    padding: 6px 13px;
}
table tr td {
    border: 1px solid #cccccc;
    text-align: left;
    margin: 0;
    padding: 6px 13px;
}
table tr th:first-child,
table tr td:first-child {
    margin-top: 0;
}
table tr th:last-child,
table tr td:last-child {
    margin-bottom: 0;
}

.CodeMirror-gutters {
    border-right: 1px solid #ddd;
}

.md-fences,
code,
tt {
    border: 1px solid #ddd;
    background-color: #f8f8f8;
    border-radius: 3px;
    padding: 0;
    font-family: Consolas, "Liberation Mono", Courier, monospace;
    padding: 2px 4px 0px 4px;
    font-size: 0.9em;
}

.md-fences {
    margin-bottom: 15px;
    margin-top: 15px;
    padding: 0.2em 1em;
    padding-top: 8px;
    padding-bottom: 6px;
}
.task-list{
	padding-left: 0;
}

.task-list-item {
	padding-left:32px;
}

.task-list-item input {
  top: 3px;
  left: 8px;
}

@media screen and (min-width: 914px) {
    /*body {
        width: 854px;
        margin: 0 auto;
    }*/
}
@media print {
    html {
        font-size: 13px;
    }
    table,
    pre {
        page-break-inside: avoid;
    }
    pre {
        word-wrap: break-word;
    }
}

.md-fences {
	background-color: #f8f8f8;
}
#write pre.md-meta-block {
	padding: 1rem;
    font-size: 85%;
    line-height: 1.45;
    background-color: #f7f7f7;
    border: 0;
    border-radius: 3px;
    color: #777777;
    margin-top: 0 !important;
}

.mathjax-block>.code-tooltip {
	bottom: .375rem;
}

#write>h3.md-focus:before{
	left: -1.5625rem;
	top: .375rem;
}
#write>h4.md-focus:before{
	left: -1.5625rem;
	top: .285714286rem;
}
#write>h5.md-focus:before{
	left: -1.5625rem;
	top: .285714286rem;
}
#write>h6.md-focus:before{
	left: -1.5625rem;
	top: .285714286rem;
}
.md-image>.md-meta {
    border: 1px solid #ddd;
    border-radius: 3px;
    font-family: Consolas, "Liberation Mono", Courier, monospace;
    padding: 2px 4px 0px 4px;
    font-size: 0.9em;
    color: inherit;
}

.md-tag{
	color: inherit;
}

.md-toc { 
    margin-top:20px;
    padding-bottom:20px;
}

.sidebar-tabs {
    border-bottom: none;
}

#typora-quick-open {
    border: 1px solid #ddd;
    background-color: #f8f8f8;
}

#typora-quick-open-item {
    background-color: #FAFAFA;
    border-color: #FEFEFE #e5e5e5 #e5e5e5 #eee;
    border-style: solid;
    border-width: 1px;
}

#md-notification:before {
    top: 10px;
}

/** focus mode */
.on-focus-mode blockquote {
    border-left-color: rgba(85, 85, 85, 0.12);
}

header, .context-menu, .megamenu-content, footer{
    font-family: "Segoe UI", "Arial", sans-serif;
}

.file-node-content:hover .file-node-icon,
.file-node-content:hover .file-node-open-state{
    visibility: visible;
}

.mac-seamless-mode #typora-sidebar {
    background-color: #fafafa;
    background-color: var(--side-bar-bg-color);
}

.md-lang {
    color: #b4654d;
}



</style>
</head>
<body class='typora-export' >
<div  id='write'  class = 'is-mac show-fences-line-number'><h1><a name='header-n157' class='md-header-anchor '></a>三代测序研究焦点⓷人类生物医学研究</h1><div class='md-toc' mdtype='toc'><p class="md-toc-content"><span class="md-toc-item md-toc-h1" data-ref="n157"><a class="md-toc-inner" href="#header-n157">三代测序研究焦点⓷人类生物医学研究</a></span><span class="md-toc-item md-toc-h2" data-ref="n160"><a class="md-toc-inner" href="#header-n160">前言</a></span><span class="md-toc-item md-toc-h3" data-ref="n163"><a class="md-toc-inner" href="#header-n163">Hidden Heritability带来的挑战</a></span><span class="md-toc-item md-toc-h3" data-ref="n166"><a class="md-toc-inner" href="#header-n166">最完整的人类遗传多样性视图</a></span><span class="md-toc-item md-toc-h2" data-ref="n169"><a class="md-toc-inner" href="#header-n169">介绍</a></span><span class="md-toc-item md-toc-h3" data-ref="n170"><a class="md-toc-inner" href="#header-n170">了解SMRT测序如何影响人类生物医学研究</a></span><span class="md-toc-item md-toc-h3" data-ref="n189"><a class="md-toc-inner" href="#header-n189">用于人类生物医学研究的Long-read解决方案</a></span><span class="md-toc-item md-toc-h2" data-ref="n208"><a class="md-toc-inner" href="#header-n208">应用</a></span><span class="md-toc-item md-toc-h3" data-ref="n211"><a class="md-toc-inner" href="#header-n211">免疫相关研究</a></span><span class="md-toc-item md-toc-h4" data-ref="n214"><a class="md-toc-inner" href="#header-n214">复合免疫基因对疾病相关研究的影响</a></span><span class="md-toc-item md-toc-h4" data-ref="n217"><a class="md-toc-inner" href="#header-n217">了解SMRT测序如何影响免疫基相关因组研究</a></span><span class="md-toc-item md-toc-h3" data-ref="n243"><a class="md-toc-inner" href="#header-n243">癌症相关研究</a></span><span class="md-toc-item md-toc-h4" data-ref="n246"><a class="md-toc-inner" href="#header-n246">SMRT测序能够提供有关癌症基因组复杂性最全面的观点</a></span><span class="md-toc-item md-toc-h3" data-ref="n266"><a class="md-toc-inner" href="#header-n266">神经科学研究</a></span><span class="md-toc-item md-toc-h4" data-ref="n269"><a class="md-toc-inner" href="#header-n269">更深入的发现</a></span><span class="md-toc-item md-toc-h2" data-ref="n295"><a class="md-toc-inner" href="#header-n295">参考文献</a></span></p></div><h2><a name='header-n160' class='md-header-anchor '></a>前言</h2><p>发现隐藏的遗传可能性；发现疾病、人群或个体特异的，在基因组中染色体级别定位的变异类型的完整谱系。</p><h3><a name='header-n163' class='md-header-anchor '></a>Hidden Heritability带来的挑战</h3><p>低成本测序的出现为我们提供了人类遗传变异在健康和疾病中的作用方面更深入的了解。 然而，由于二代测序技术短读长的局限性，大多数研究仅报告单核苷酸变异（Single Nucleotide Variants，SNV）和小型InDel事件，并且丢失较大的结构变异和其他复杂的基因组元件信息[<a href='#ref1'>1</a>]。非SNV的DNA变异占人类基因组中所有变异碱基的74％[<a href='#ref2'>2</a>]，并且可能对揭示疾病表型与潜在基因型的关系至关重要。</p><h3><a name='header-n166' class='md-header-anchor '></a>最完整的人类遗传多样性视图</h3><p>SMRT测序通过无与伦比的读长、均衡的覆盖和超高的精确度提升人类遗传多样性研究的效果：可以发现之前隐藏的变异并直接得到跨单倍型域的定位信息。利用Sequel系统，科学家们可以得到疾病遗传性在遗传学方面的新见解。</p><h2><a name='header-n169' class='md-header-anchor '></a>介绍</h2><h3><a name='header-n170' class='md-header-anchor '></a>了解SMRT测序如何影响人类生物医学研究</h3><p><img src='http://www.pacb.com/wp-content/uploads/2015/06/Spotlight01_Research_Human2.jpg' alt='' /></p><ul><li>通过在研究设计中包含结构变异和等位基因多样性，拓展<a href='http://www.pacb.com/wp-content/uploads/Case-Study-Human-Improving-Precision-Medicine-Studies-in-Asia-Using-Ethnicity-Specific-Human-Reference-Genomes-and-PacBio-Long-Read-Sequencing.pdf'>精准医学</a>的效果、改善人体健康</li><li>通过详细地表征复杂基因和单倍型进行<a href='#Hidden'>免疫疾病联合</a>研究</li><li><a href='#Cancer'>驱动癌症发现</a>，获得更完整的基因组癌症景观</li><li><a href='19.html'>表征病原体及其其移动组分、与宿主的相互作用、群体和起源</a>，以发现和设计更好的疫苗、治疗和预后</li><li>发现和了解<a href='http://www.pacb.com/wp-content/uploads/Kujawa-ASHG-2016-Alzheimer%E2%80%99s-Disease-Candidate-Genes-and-Transcripts-Using-Hybridization-Capture.pdf'>神经系统疾病</a>的生物学致病机制</li></ul><h3><a name='header-n189' class='md-header-anchor '></a>用于人类生物医学研究的Long-read解决方案</h3><p><img src='http://www.pacb.com/wp-content/uploads/2015/06/01_HumanSpot01.jpg' alt='' /></p><ul><li><a href='12.html'>精准靶向和表征遗传疾病的复杂区域</a></li><li>在完整图谱的尺寸上以单碱基对的分辨率解析<a href='10.html'>结构变异</a></li><li>用<a href='18.html'>全长转录组测序</a>研究同种型多样性</li><li>通过敏感的<a href='16.html'>低频病毒和体细胞变异的单倍型分析</a>进行致病性、进化和选择的相关研究</li><li>创建疾病、人群或个人特异的<a href='10.html'>金标准参考基因组</a></li></ul><h2><a name='header-n208' class='md-header-anchor '></a>应用</h2><p><span id="Hidden"></span></p><h3><a name='header-n211' class='md-header-anchor '></a>免疫相关研究</h3><p>对人类遗传学和疾病相关研究使我们对此有更深入理解的同时，也加深了对遗传性与免疫相关疾病之间联系的研究需求。人类主要组织相容性复合物（Major Histocompatibility Complex，MHC）和与许多免疫相关疾病有关的杀伤免疫受体（Killer Immune Receptor，KIR）之间存在有充分证据证明的关联性；研究这些关联激发了对各种先进测序工具和大型队列研究的大量投资。 尽管做了这些努力，MHC或KIR中相关变异的精细定位仍然很困难，限制了我们对导致免疫疾病的机制的理解[<a href='#ref3'>3</a>]。</p><h4><a name='header-n214' class='md-header-anchor '></a>复合免疫基因对疾病相关研究的影响</h4><p>免疫亚基因组区域固有的复杂性是一个挑战，它可能是将相关变异与免疫疾病联系起来的原因。 MHC和KIR基因复合物含有大量拷贝数变异（Copy Number Variant，CNV）、高密度基因、超多态性等位基因和具有巨大连锁不平衡（Linkage Disequilibrium，LD）的保守扩增单倍型（Conserved Extended Haplotypes，CEH）。 这种复杂程度使得使用二代测序方法难以正确地组装或比对这些单倍型[<a href='#ref4'>4</a>]。</p><h4><a name='header-n217' class='md-header-anchor '></a>了解SMRT测序如何影响免疫基相关因组研究</h4><p><img src='http://www.pacb.com/wp-content/uploads/Spotlight_Human_Immunology.jpg' alt='' /></p><p>利用SMRT技术提供的Long-read、覆盖均匀和准确度高、一致性好的测序，可以全面、完整地解析在复杂免疫区域观察到的序列变异。</p><ul><li>检测<a href='15.html#header-c335'>整个HLA基因</a>的全谱多态性</li><li>表征保守的<a href='15.html#header-c397'>扩展型MHC单倍型</a></li><li>同时为<a href='15.html#header-c397'>KIR基因复合物鉴定基因型和单倍型</a></li><li><a href='http://onlinelibrary.wiley.com/doi/10.1111/bjh.14180/full'>免疫球蛋白所有组成成分多样性</a>的全长检测</li></ul><p><strong>特色研究：</strong>探索复杂免疫基因座（如KIR基因）的遗传变异[<a href='#ref5'>5</a>]</p><p><img src='http://www.pacb.com/wp-content/uploads/Prall-2017-Improved-full-length-KIR-transcript-discovery-in-Mauritian-cynomolgus-macaques-Fig-4.jpg' alt='' /></p><p>科学家使用Long-read在Cynomolgus macaques的well-characterized群体中鉴定明确的KIR基因型。 他们确定了9种新颖的等位基因变异体，这些变异体辅助了Mafa-KIR单倍型组织模型的改良（如上所示）。</p><p><span id="Cancer"></span></p><h3><a name='header-n243' class='md-header-anchor '></a>癌症相关研究</h3><p>低成本的测序能够进行广泛的基因组研究，这些研究也已经发现了许多癌症类型中存在的SNV，然而，癌症基因组还包括大规模结构变异，例如大的插入、缺失、逆转、重复、易位和基因融合，这些突变类型中的大多数都还没得到很好的研究，相当于在癌症发展与治疗的研究中留下了空白[<a href='#ref6'>6</a>]。</p><h4><a name='header-n246' class='md-header-anchor '></a>SMRT测序能够提供有关癌症基因组复杂性最全面的观点</h4><ul><li>通过<a href='18.html'>对Iso-form多样性的完整检测</a>（包括基因融合、剪接位点和内含子等）发现癌症样本中隐藏的生物学机制；</li><li><a href='10.html'>以极高的分辨率检测SV</a>，包括CNV的基因组背景、插入/缺失/倒位/易位的准确断点以及不稳定的微卫星标志物的完整序列；</li><li>靶向检测基因或大型基因组的特定区域，<a href='16.html#header-c55'>直接检测其变异</a>，揭示耐药机制；</li><li><a href='http://onlinelibrary.wiley.com/doi/10.1111/bjh.14180/abstract'>更完整的测序</a>帮助还原更全面的免疫反应原貌。</li></ul><p><strong>特色研究</strong>：Iso-Seq方法揭示前列腺癌中受体的活性</p><p><img src='http://www.pacb.com/wp-content/uploads/Kohli-2017_Figure-4A_July-2017_MA-Request.jpg' alt='' /></p><p>雄性激素受体Isoform的靶向SMRT测序显示，以前的AR-V9结构是错误的，忽略了被认为只出现在AR-V7中的隐性外显子。 AR-V7作为基于敲除实验的耐药性的潜在生物标志物，其实际上靶向了两种Isoform，新数据表明AR-V9实际上可能是更具预测性的Isoform[<a href='#ref7'>7</a>]。</p><h3><a name='header-n266' class='md-header-anchor '></a>神经科学研究</h3><p>为了确定神经系统、神经肌肉和神经退行性疾病的基因驱动因素，研究者必须采用新的工具来得到完整的基因组信息——包括先前认为不可能进行测序的区域。</p><h4><a name='header-n269' class='md-header-anchor '></a>更深入的发现</h4><ul><li>使用预先设计的捕获模板或长链PCR靶向<a href='12.html'>捕获候选基因</a>，富集并测序长达几Kb的序列片段；</li><li>检测等位基因、<a href='10.html'>筛选变异</a>，包括SNP和复杂SV（如重复扩增和长均聚物）；</li><li>检测疾病相关转录本Isoform的<a href='18.html#header-c11'>完整序列</a>，以完整表征特定基因的转录本；</li><li>检测<a href='17.html#header-c43'>表观遗传学特征</a>，以更全面地了解潜在的生物疾病机制。</li></ul><p><strong>特色研究：</strong>对FMR1基因Isoform进行研究以检测选择性剪接</p><p><img src='http://www.pacb.com/wp-content/uploads/Pretto-2015_Figure-5.jpg' alt='' /></p><p>科学家建立了FMR1基因Isoform的第一个综合图谱，以了解可变剪接在Fragile X associated Tremor/Ataxia Syndrome发展中的作用。 该研究突出显示两个转录本的差异表达，并显示RNA毒性可能是由FMR1前置载体中所有Isoform的一般过表达引起的[<a href='#ref8'>8</a>]。 </p><p><strong>特色研究：</strong>在阿尔茨海默病中产生的单体型特异性变异</p><p><img src='http://www.pacb.com/wp-content/uploads/Kajawa-2017_Figure-6.png' alt='' /></p><p>研究者利用35个候选基因的靶向测序检测阿尔茨海默氏病患者的基因组变异。 使用SMRT测序，他们发现了新的转录本Isoform，一种新的，与特定等位基因相关的外显子和相位变异及其随后产生的Isoform[<a href='#ref9'>9</a>]。</p><h2><a name='header-n295' class='md-header-anchor '></a>参考文献</h2><p><span id="ref1">[1] <a href='http://www.g3journal.org/content/4/1/63.short'>Pang, A., <em>et al</em>., (2014) Performance of high-throughput sequencing for the discovery of genetic variation across the complete size spectrum. <em>G3</em>. 4(1), 63-65</a>.</span></p><p><span id="ref2">[2] <a href='http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0050254'>Levy, S., <em>et al</em>., (2007). The diploid genome sequence of an individual human. <em>PLOS Biology</em>. 5(10), e254</a>.</span></p><p><span id="ref3">[3] <a href='http://www.ncbi.nlm.nih.gov/pubmed/23875801'>Trowsdale J. and Knight JC., (2013) Major histocompatibility complex genomics and human disease. <em>Annual Review Genomics Human Genetics.</em> 14, 301-323</a>.</span></p><p><span id="ref4">[4] <a href='http://www.ncbi.nlm.nih.gov/pubmed/25787242'>Brandt, D. Y. C., et al., (2015) Mapping bias overestimates reference allele frequencies at the <em>HLA</em> genes in the 1000 Genomes Project phase I data. 5(5), 931-941</a>.</span></p><p><span id="ref5">[5] <a href='https://www.ncbi.nlm.nih.gov/pubmed/28343239'>Prall, T. M., et al., (2017) Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques. <em>Immunogenetics</em> doi:10.1007/s00251-017-0977-7.</a></span></p><p><span id="ref6">[6] <a href='http://www.ncbi.nlm.nih.gov/pubmed/23539594'>Vogelstein, B., et al., (2013) Cancer Genome Landscapes. <em>Science.</em> 339(6127), 1546-1558</a>.</span></p><p><span id="ref7">[7] Kohli, M. et al., 2017. <a href='http://clincancerres.aacrjournals.org/content/early/2017/06/26/1078-0432.CCR-17-0017.long'>Androgen receptor variant AR-V9 is co-expressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance.</a> <em>Clinical Cancer Research</em>, ePub ahead of print.</span></p><p><span id="ref8">[8] Pretto, D.I. et al., 2015. <a href='https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394606/pdf/nihms-677775.pdf'>Differential increases of specific FMR1 mRNA isoforms in premutation carriers</a>. <em>Journal of Medical Genetics</em>, 52(1), pp.42–52.</span></p><p><span id="ref9">[9] Kujawa, S. et al., 2016. <a href='http://www.pacb.com/wp-content/uploads/Kujawa-ASHG-2016-Alzheimer%E2%80%99s-Disease-Candidate-Genes-and-Transcripts-Using-Hybridization-Capture.pdf'>A method for the identification of variants in Alzheimer’s disease candidate genes and transcripts using hybridization capture combined with long-read sequencing</a>. In <em>66th Annual Meeting of the American Society of Human Genetics</em>. Vancouver, BC.</span></p></div>
</body>
</html>